Current Medical Management of Glaucoma

Mechanism

Beta-blockers decrease aqueous humor production by the ciliary body and hence reduce IOP. Evidence suggests that this occurs only during the day and not during sleep. This may be important in patients who experience some of the systemic side effects (e.g., lower blood pressure and pulse rate) at night, with the potential for disease progression without other therapy to reduce IOP.

Efficacy

Beta-blockers are effective topical agents, with the mean peak IOP reduced by 25% and the mean trough reduced by 20% using nonselective agents. In general, nonselective agents lower IOP equally effectively. With betaxolol, a β ₁ -selective agent, IOP reduction is slightly less. None of the beta-blockers should be used more than twice daily. Certain nonselective agents, including timolol, may be used once daily, preferably in the morning. Once-daily instillation may be more convenient for the patient, which enhances compliance and reduces the amount of drug used. Furthermore, many agents are available in more than one concentration. Lower concentrations are preferred and are as effective in the majority of patients. Unfortunately, no studies have proven that lower concentrations have a lower incidence of side effects or produce less severe side effects.

Side Effects

Contraindications to beta-blocker use include asthma, severe chronic obstructive pulmonary disease, bradycardia, second- or third-degree heart block, and congestive heart failure. Clinically it is prudent not to use this class of drug in any patient who has reactive airway disease (asthma), has a heart rate of less than 55 beats/min, has or has had heart failure, has a history of present or past use of antidepressant medications, or has impotence. A positive history of cardiac problems or symptoms is usually present in patients who have greater than first-degree heart block.

Although cardiac and pulmonary side effects are the most obvious, in a large review, central nervous system problems were the most frequent, ranging from hallucinations to depression to a general feeling of malaise. These side effects may be much more difficult to identify. In the majority of patients, if the drug used may be causing or exacerbating such problems, it is stopped to establish whether the symptoms improve. Older adults appear to be at the greatest risk for beta-blocker side effects. A conscious effort is required to identify susceptible patients in line with the overall philosophy of individualization of therapy and specific assessment of drug effects. Other systemic side effects of topical beta-blockers, including alopecia, a dermatological problem, are rare.

Locally, beta-blockers are very well tolerated, although corneal hypesthesia and epithelial changes have been reported. In addition, some investigators believe that their use should be avoided in patients with diabetes because the symptoms of hypoglycemia may be masked and those of myasthenia gravis may be exacerbated. Furthermore, it has been suggested that patients who are undergoing allergy tests or desensitization should not use beta-blockers of any kind, even topical agents, because beta-blockade may make resuscitation more difficult should anaphylaxis occur. The use of beta-blockers in neonates is avoided because apnea may develop. The implication that beta-blockers may have an undesirable effect on plasma lipids is less well understood. Systemic beta-blockers are known to result in undesirable changes in plasma lipid profiles. However, systemically, they are actually protective when the clinical outcomes of elevated plasma lipids (i.e., heart attack and stroke) are considered because of their positive effect on cardiovascular function. Topical timolol and, to a lesser extent, carteolol reduce high-density lipoproteins by 9% and 3%, respectively; however, no data indicate that this results in a higher risk for cardiovascular disease. Although it is true that topical beta-blockers are effective and well tolerated by the majority of patients, it is the clinician's obligation to identify patients who may benefit most from their use and those in whom their use should be avoided and other classes of agents should instead be used.

Mechanism

Apraclonidine decreases aqueous production but is also associated with an increase in outflow facility and a decrease in episcleral venous pressure. Brimonidine is 23 times more α ₂ selective than apraclonidine and 12 times more selective than clonidine. Its mechanism of action includes a reduction in aqueous formation and an increase in uveoscleral outflow.

Efficacy

The first clinical use of apraclonidine was to decrease IOP in the prevention of pressure spikes after anterior segment laser surgery. It was shown to be effective for this purpose after argon laser trabeculoplasty, argon laser iridectomy, neodymium-doped:yttrium–aluminum–garnet (Nd:YAG) laser iridotomy, Nd:YAG laser capsulectomy, and even cataract surgery and trabeculectomy. In addition, it was used successfully in cases of acute angle-closure glaucoma and as prophylaxis against high IOP spikes after cycloplegia. Apraclonidine is rarely used in the chronic treatment of glaucoma.

Brimonidine 0.5% prevents the increase in postoperative IOP after laser trabeculoplasty. Spikes greater than 10 mm Hg occurred in 1%–2% of cases using brimonidine versus 23% using vehicle. In a 12-month comparison of twice-daily brimonidine 0.2% versus timolol 0.5%, both were found to be equally effective at the 2-hour peak. No tachyphylaxis was seen with either drug over the 12 months of the study. At trough (12 hours), IOP reduction was 3.7–5.0 mm Hg with brimonidine, compared with 5.8–6.6 mm Hg with timolol. There was no difference between the groups in terms of optic disc and visual field, which were unchanged in 94% of patients. Brimonidine is approved for use three times a day but is commonly used twice daily because at the morning trough, there is no difference in IOP between the two regimens. Adherence rates are better in the three times a day group (72% ± 19%) compared with three times a day (62% ± 16%). However, dose frequency is higher in the three times a day group, 1.9 ± 0.5 versus 1.4 ± 0.4 per day. Lower concentrations of brimonidine (0.15% and 0.1%) are also available with Purite as the preservative (Alphagan P), demonstrating similar IOP-lowering efficacy to brimonidine 0.2%.

Side Effects

Chronic use of apraclonidine is limited by the risk for allergic reaction ( Fig. 10.22.1 ), which may be severe. Previous studies using apraclonidine 1% reported a variable incidence of allergic reaction of up to 48%. Systemically, this drug is well tolerated, with the primary systemic side effect being dry mouth. Brimonidine shows no effect on mean heart rate, mean blood pressure, or pulmonary function. In the longer term (6- and 12-month studies of brimonidine compared with timolol), adverse effects included dry mouth in 30% of patients and fatigue/drowsiness in 15.8% (as a result of which 2.5% of patients left the study), compared with 13.6% with fatigue ( p ≡ 0.342) in the timolol groups.

Ocular effects included conjunctival blanching in 11%–17% (vehicle, 9%) of cases and burning/stinging in 24% (timolol, 41%). Within this class of agents, the allergy often limits the drug's clinical usefulness. The allergic response caused by brimonidine 0.2% is approximately 5% at 3 months and 12% at 12 months. Different formulations of brimonidine are available that reduce the concentration to 0.15% or 0.1% and replace benzalkonium chloride with a proprietary Purite preservative. The most significant clinical improvement with the lower concentrations is a reduced incidence of allergic reactions by more than 50% (7.1% vs. 17.1%). Use of the Purite preservative could be a great advantage to patients in whom benzalkonium chloride causes ocular surface disruption. This includes patients who are particularly sensitive to the preservative, as well as patients taking multiple drops in whom toxicity may be cumulative.

Brimonidine has been suggested to have potential neuroprotective effects on the optic nerve and retinal ganglion cells. Animal data supporting this claim are extensive. The results of a single trial in humans (Low-Pressure Glaucoma Treatment Study) demonstrated significantly greater preservation of visual field after 4 years in patients with low-pressure glaucoma successfully treated with brimonidine 0.2% compared with timolol 0.5% despite similar and minimal IOP reduction in both groups.

Brimonidine is generally contraindicated in children because of the risk of potential side effects, such as bradycardia, hypotension, hypothermia, hypotonia, lethargy, and apnea.